Oricula Therapeutics Product History
Oricula Therapeutics' first product (ORC-13661), a medicine to preserve hearing during aminoglycoside therapy, is in preclinical development and progressing towards an FDA Initial New Drug (IND) filing.
Our initial screening hit, ORC-0001 (also formerally known as BPN-0001 and PROTO-1), was effective in zebrafish and rats in protecting hair cells from the toxic effects of aminoglycosides (AGs), but ADMET testing and especially hERG tests showed that the safety margin of ORC-0001 was not adequate to progress it as a medicinal candidate.
Funding provided by NIDCD and the NINDS Blueprint Neurotherapeutics Program (NIH BPN) allowed us to engage in an extensive SAR (structure activity relationship) program. In all, we synthesized and tested 329 analogs of ORC-0001 and found 50 analogs that were 10 times more potent and 10 analogs that were 100 times more potent than the initial lead in protecting zebrafish hair cells. Additional testing and analysis established that five compounds had the selectivity (based on broad screening), potency, efficacy, pharmacokinetic and physiochemical properties along with chemical novelty to advance the project to late lead optimization. In parallel, we confirmed that none of these compounds interfere with the bactericidal efficacy AGs.
University of Washington was awarded a Composition of Matter patent on these and related compounds, and Oricula Therapeutics has an exclusive license from the University to develop and commercialize these assets.
ORC-13661 was chosen as the lead clinical candidate after extensive efficacy testing in using the ABR analysis. ORC-13661 at an oral dose of 5mg/kg/day provided 100 percent protection of hearing for rats treated for 10 days with amikacin at 320 mg/kg/day administered subcutaneously. It also provided almost complete hearing protection for rats treated for 12 days at the same dose of amikacin. Additional testing of ORC-13661 shows that it provides:
Adequate oral bioavailability in mice, rats and dogs
Linear pharmacokinetics in a range of 0.2 mg/kg - 100 mg/kg
A half-life of 4-6 hours, providing adequate coverage for once/day therapy
AMES testing demonstrated no evidence of mutagenicity
Microsomal and Hepatocyte Clearance consistent with the half-life in serum
A metabolic profile similar in rat, dog, monkey and human with no unique human metabolites
A NOAEL in the rat 7-day DRF study of > 100 mg/kg, providing a wide therapeutic index
Additional in vitro testing showed no interference with aminoglycoside bactericidal effect in P. auruginosa, E.coli, or M.tuberculosis.
Oricula Therapeutics has been awarded a Phase 2 SBIR grant by NIH NIAID to advance ORC-13661 through preclinical safety and toxicology to FDA IND submission.